The Mitochondrial A10398G Polymorphism, Interaction with Alcohol Consumption, and Breast Cancer Risk

Abstract

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.

Tea Consumption, Alcohol Drinking and Physical Activity Associations with Breast Cancer Risk among Chinese Females: a Systematic Review and Meta-analysis

“…For example, the reported prevalence rate of alcohol drinking among Chinese female had increased from 2.58% in 1993 (PRC, 1995) to 4.5% in 2002 (Ma et al, 2005) (Yu et al, 1995) and estrogen (Taioli et al, 1996) had also been reported to affect the relationship between alcohol drinking and breast cancer in different ethnics. For example, 10398G allele in the mitochondrial genome was reported to influence the alcohol metabolism, which may also modify the association between alcohol drinking and breast cancer (Pezzotti et al, 2009). Additionally, consistent J-shaped curve of alcohol drinking on the risk of diseases was found in many cardiovascular diseases (White et al, 1999;Gmel et al, 2001).…”

Mitochondrial Genome Instability in Cancer

“…Mt-polymorphisms pinpointed for increased risk were: G9055A, A10398G, and T16519C, whereas T3197C and G13708A lowered the risk for breast tumors. In a provocative study recently reported by Pezzotti et al [2009] on a series of 1,561 breast cancer cases and 2,209 matched controls of predominantly European-American ancestry, the authors observed an interaction between breast malignancy, alcoholism, and A10398G allele. The combination of this allele with augmented alcohol consumption produced 56% increased risk for breast cancer with regard to the risk shown by non-drinking females carrying the same variant.…”

Antioxidant Enzymes as New Biomarkers for Prediction of Tumor Progression in Breast Cancer

“…In humans, several studies have shown a relatively high frequency of mtDNA mutations in breast tumor tissues (range 20%-93%) . Among them, we have cited above the A10398G (T114A) polymorphism in the NADH dehydrogenase subunit gene of the mitochondrial genome (Pezzotti et al, 2009). In consequence, a persistent dysfunction of mitochondrial respiratory chain is a source of ROS production in breast carcinoma cells.…”